CN102311402A - Preparation method of 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone - Google Patents

Preparation method of 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone Download PDF

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CN102311402A
CN102311402A CN201110200714A CN201110200714A CN102311402A CN 102311402 A CN102311402 A CN 102311402A CN 201110200714 A CN201110200714 A CN 201110200714A CN 201110200714 A CN201110200714 A CN 201110200714A CN 102311402 A CN102311402 A CN 102311402A
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substituted
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ester
phenyl
oxazolidine
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沈建伟
吴和明
朱崇泉
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Suzhou Jingye Medicine & Chemical Co Ltd
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Abstract

The invention discloses a preparation method of 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone. Substituted aniline which is treated as an initial substance is condensed with glycidol to synthesize an intermediate (R)-(+)-3-substituted phenylamino-1,2-propylene glycol, and a two-step reaction is carried out to prepare 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone. The obtained product 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone is an important intermediate for commercial production of oxazolidinone antiseptics. The preparation method of 3-substituted phenyl-5-hydroxymethyl oxazolidine-2-ketone with the two-step reaction which has the characteristics of less step, simple operation, easily obtained and cheap raw material, mild reaction condition and the like, and has the advantages of improvement of the production efficiency, reduction of the production energy consumption, improvement of the production safety coefficient, reduction of the production cost, and reduction of the environmental pollution is a synthetic method with environmental protection and low carbon.

Description

The preparation method of 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, be specifically related to a kind of preparation method of key intermediate 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone of Zhi oxazolidinones antiseptic-germicide.
Background technology
Oxazolidine ketone antiseptic-germicide is the antibacterial agent that one type of mechanism of action is different from other various antiseptic-germicides.3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone is that the synthetic necessary key intermediate of this type medicine is (referring to Steven JB, et a1.J Med Chem, 1996,39 (3): 673-679; Meng Qingguo, Wang Qi, Liu Jun, Acta Pharmaceutica Sinica, 2003,38 (10): 754～759; Barbachyn, MR etc., WO9507271; Barbachyn, MR etc., ZL94193313.x; The pendant Germania, BA etc., ZL97193658.7; The pendant Germania, BA etc., ZL01133003.1; Xu Guangyu etc., ZL200410017127.0; Barbachyn, MR etc., ZL200510048548.4).
In the prior art; The preparation method of 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone; Most of substituted anilines that adopt react with chloroformic acid benzyl ester earlier, and the substituted-phenyl-benzyl carbamate of generation reacts (Steven JB, et a1.J Med Chem with the Racemic glycidol butyric ester again; 1996,39 (3): 673-679; ZL94193313.x, WO9507271; Acta Pharmaceutica Sinica, 2003,38 (10): 754～759), reaction formula is following:
The reaction conditions of this method is relatively harsher, needs to use butyllithium reagent and very low temperature (78 ℃); When suitability for industrialized production; The Pei Erman of Pharmacia & Upjohn S.P.A etc. improves reaction; Temperature of reaction can be elevated to-10 ℃～-28 ℃ (ZL01133003.1, ZL03159474.3, ZL97193658.7); And with S-(+)-3-chloro-1,2-Ucar 35 or Racemic glycidol replace the Racemic glycidol butyric ester, and production technique is more simple.Reaction formula is following:
Figure 2011102007143100002DEST_PATH_IMAGE004
The Xu Guangyu of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences etc. are with (S)-Glycerose reaction of substituted aniline and acetone protection; The imines that generates is with 10% palladium-hydrocarbonize; Use hydrogenchloride ethanol deprotection base then, obtain 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone (ZL200410017127.0) with the TRIPHOSGENE 99.5 cyclization at last; Though this method does not re-use the such reagent of butyllithium, step is more, and is cumbersome; Reaction formula is following:
Figure 2011102007143100002DEST_PATH_IMAGE006
Product III wherein is not disclosed in this article.
The Huang Qiang of Zhengzhou University etc. use substituted aniline and phosgene reaction to generate the substituted-phenyl isocyanide ester; React with Glycidyl butyrate then; Last sodium bicarbonate aqueous solution hydrolysis obtains 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone (ZL200510048548.4), and this method need be used lithiumbromide and tributyl phosphorus oxide.Reaction formula is following:
Figure 2011102007143100002DEST_PATH_IMAGE008
There are various deficiencies in aforesaid method, some method severe reaction conditions, and some method steps is complicated; And its common shortcoming is to use the carbon atom utilization ratio of reagent lower, for example, chloroformic acid benzyl ester the earliest-Racemic glycidol butyric ester route, the carbon atom utilization ratio of reagent chloroformic acid benzyl ester has only 1/8, and total atom utilization also has only 1/9; The carbon atom utilization ratio of Racemic glycidol butyric ester is 3/7, and total atom utilization is 5/11.Chloroformic acid benzyl ester after the improvement-3-propylene glycol of chlorine route does not change the atom utilization of chloroformic acid benzyl ester, is that atom utilization is very high and use 3-propylene glycol of chlorine great advantage, and total atom utilization brings up to 11/13; The glycidaldehyde route of domestic scholars improvement, the carbon atom rate of glycidaldehyde has only 1/2; And the isocyanide ester route has used the not high Racemic glycidol butyric ester of atom utilization.The carbon atom utilization ratio is not high, means to have produced organic by-products in the reaction process, and therefore, also just meaning has wasted resource, and has caused the pollution of environment, and not only production cost is higher, does not also meet low-carbon (LC), environment-friendly and green synthetic development trend.
Summary of the invention
Goal of the invention of the present invention provides the preparation method of a kind of 3-substituted-phenyl-5-hydroxyl first base oxazolidine-2-ketone, when simplifying preparation technology, making reaction conditions gentle, improves the utilization ratio of carbon atom, to reduce the pollution to environment.
For reaching the foregoing invention purpose, the technical scheme that the present invention adopts is: the preparation method of a kind of 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone, and the structural formula of said 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone is:
Figure 2011102007143100002DEST_PATH_IMAGE010
In the formula, R 1Be halogen, preferred fluorine; R 2Be nitrogen heterocyclic ring or replacement aromatic ring;
Said nitrogen heterocyclic ring is
Figure 2011102007143100002DEST_PATH_IMAGE012
or
Figure 2011102007143100002DEST_PATH_IMAGE014
Z in the formula 1Be O, S or NR 4R 4Be amine protecting group, like benzyl, substituted benzyl, formic acid ester group, carboxylic acyl radical, alkylsulfonyl; Z 1Preferred O or S;
R 3Alkyl for C1-C4;
Said replacement aromatic ring is
Figure 2011102007143100002DEST_PATH_IMAGE016
Z wherein 2Be CH 2Or N; R 5For
Figure 2011102007143100002DEST_PATH_IMAGE018
Or
Figure 2011102007143100002DEST_PATH_IMAGE020
,
R wherein 6Alkyl for C1-C6; R 7Be amine protecting group, like benzyl, substituted benzyl, formic acid ester group, carboxylic acyl radical, alkylsulfonyl; R 8Be amine protecting group, like benzyl, substituted benzyl, formic acid ester group, carboxylic acyl radical, alkylsulfonyl;
Substituted aniline with structural formula II is a raw material,
Figure DEST_PATH_IMAGE022
R in the formula 1, R 2Definition the same,
Amino-1 through synthetic midbody (R)-(+)-3-substituted benzene that obtains of condensation reaction with Racemic glycidol, 2-Ucar 35, the structural formula of said Racemic glycidol do,
Figure DEST_PATH_IMAGE024
Said (R)-(+)-3-substituted benzene is amino-1, and the structural formula of 2-Ucar 35 does,
Figure DEST_PATH_IMAGE026
R in the formula 1, R 2Definition the same,
With the reaction of compound III and carbonyl derivative, promptly obtain target compound again, the structural formula of said carbonyl derivative does,
Figure DEST_PATH_IMAGE028
Wherein, X 2, X 3Be leavings group, be selected from halogen, the substituted C1 of halogen～C4 alkoxyl group, benzyloxy ,Phenoxy, ortho position or a position or contraposition halogen or substituted phenoxy of nitro or imidazolyl, X 2, X 3Can be identical, also can be different.
Technique scheme can be expressed as:
In the technique scheme, in said substituted aniline and the Racemic glycidol reaction, substituted aniline is 0.8～5:1 with the ratio of the amount of substance of Racemic glycidol; Used organic solvent is selected from alcohol, ether or methane amide; Temperature of reaction is 20～100 ℃.
Optimized technical scheme, substituted aniline is that the used organic solvent of 0.8～1.5:1 is selected from methyl alcohol, ethanol, Virahol, ether, THF, DIPE or DMF with the ratio of the amount of substance of Racemic glycidol; Temperature of reaction is 60～80 ℃.
In the technique scheme, (R)-(+)-3-substituted benzene amino-1, the 2-Ucar 35 is 1:1～2 with the ratio of the amount of substance of carbonyl derivative; Used organic solvent is selected from alcohol, ether or methane amide; Temperature of reaction is-20～20 ℃.
Optimized technical scheme, (R)-(+)-3-substituted benzene amino-1, the 2-Ucar 35 is 1:1.5 with the ratio of the amount of substance of carbonyl derivative; Used organic solvent is selected from methyl alcohol, ethanol, Virahol, ether, THF, DIPE or DMF; Temperature of reaction is-5～5 ℃.
Further technical scheme, (R)-(+)-3-substituted benzene amino-1, in 2-Ucar 35 midbody and the carbonyl derivative VI reaction process, add de-acidying agent, de-acidying agent is selected from mineral alkali or organic bases; The mol ratio of de-acidying agent and midbody is 0～4:1.
Preferably, de-acidying agent is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, pyridine, quinoline or triethylamine; The mol ratio of de-acidying agent and midbody is 0～2.4:1.
In the technique scheme, according to X 2, X 3It can be halogen; Like chlorine, bromine; Also can be halogen substituted alkoxy, other substituted alkoxyl group etc.; According to different combinations, said carbonyl derivative be selected from the adjacent chlorobenzene ester of phosgene, two phosgene, TRIPHOSGENE 99.5, methyl-chloroformate, Vinyl chloroformate, propyl chloroformate, butyl chlorocarbonate, chloroformic acid benzyl ester, methylcarbonate, diethyl carbonate, dipropyl carbonate, dibutyl carbonate, phenyl chloroformate, chloroformic acid, chloroformic acid to chlorobenzene ester, chloroformic acid m-chlorophenyl ester, the adjacent bromobenzene ester of chloroformic acid, chloroformic acid to bromobenzene ester, chloroformic acid bromochlorophene ester, chloroformic acid ortho-nitrophenyl ester, p-nitrophenyl chloroformate ester, chloroformic acid nitroxyl chloride phenyl ester, diphenyl carbonate, the two adjacent chlorobenzene esters of carbonic acid, the two m-chlorophenyl esters of carbonic acid, carbonic acid biconjugate chlorobenzene ester, the two adjacent bromobenzene esters of carbonic acid, carbonic acid two between bromobenzene ester, carbonic acid biconjugate bromobenzene ester, the two o-chloronitrobenzene esters of carbonic acid, the two m-nitro esters of carbonic acid, carbonic acid biconjugate nitro phenyl ester or phosphinylidyne diimidazole.
Preferably, said carbonyl derivative is selected from TRIPHOSGENE 99.5, two phosgene, phosgene, chloroformic acid benzyl ester, methyl-chloroformate, Vinyl chloroformate or phosphinylidyne diimidazole.。
In the technique scheme; The reagent Racemic glycidol that uses (structural formula V) be configured as the S configuration; Midbody (R)-(+)-3-substituted benzene amino-1; 2-Ucar 35 (structural formula II I) be configured as the R configuration, product 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone (general formula I) be configured as the R configuration.
Product of the present invention is that synthetic Linezolid (Linezolid), thunder get azoles amine (Radezolid), the appropriate useful key intermediate that draws azoles amine (Torarolide), thunder shellfish azoles amine oxazolidine ketone antiseptic-germicides such as (Ranbezolid).
Because the technique scheme utilization, the present invention compared with prior art has advantage:
The present invention is a raw material with the substituted aniline of structural formula II, through midbody (R)-(+)-3-substituted benzene amino-1,2-Ucar 35; The method of the 3-substituted-phenyl-5-Qiang Jia Ji oxazolidine-2-ketone of two step prepared in reaction general formula Is and literature method comparison have that step is few, simple to operate, raw material is cheap and easy to get, reaction conditions is gentle, have avoided such as butyllithium, the such reagent of potassium tert.-butoxide; And very low temperature, absolute anhydrous so harsh reaction conditions, not only reaction efficiency is high, energy consumption is low, and has improved the safety in production coefficient; Reduced production cost, simultaneously, the present invention prepares employed reagent atom utilization height in the process; The carbon atom utilization ratio reaches 100%, therefore, does not produce organic by-products in the production process; Unique side product sodium-chlor, environmental pollution is little.
Therefore, combined coefficient of the present invention is high, and energy consumption is low, and three-waste pollution is few, is that a kind of environmental protection is friendly, the green synthesis method of low-carbon (LC).
Embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one:
At 500ml stirring is housed, adds 3-fluoro-4-(4-morpholinyl) aniline 29.4g (0.15mol) in the four-hole bottle of condensing surface and TM, (S)-Racemic glycidol 7.4g (0.1mol) and 200ml ethanol, stirring heating backflow 12hrs.
Decompression removes solvent, adds 200ml water, stirs 1hr.Suction filtration, the aqueous solution of compound (2), can directly be used for step ring-closure reaction down.Through quantitative analysis, include (R)-(+)-3-(3-fluoro-4-morpholine phenylamino)-1,2-Ucar 35 23.11g.Yield 85.6%.
Figure DEST_PATH_IMAGE036
At 1000ml stirring is housed, adds the about 350ml of the aqueous solution (0.0854mol) that includes 23.11g compound (2) in the instance 1,100ml ethylene dichloride in the four-hole bottle of tap funnel and TM.Bathe under the cooling at cryosel, control liquid temperature slowly drips the dichloroethane solution 120ml (0.11mol) that contains the 11g TRIPHOSGENE 99.5 at 0～5 ℃.Drip and finish, at 5 ℃ of following insulated and stirred 1hr.Under this temperature, drip 100g 15% aqueous sodium hydroxide solution then.Drip and finish, be warming up to room temperature, insulated and stirred 2hrs.
Reaction finishes, and standing demix is obtained organic layer, and water is with 150ml * 2 ethylene dichloride extraction secondary.Abandon water, merge organic phase, once with the water washing of 100ml saturated common salt.
Decompression removes ethylene dichloride, takes off to 100ml to add the 200ml aqueous solution that contains 10g 36% hydrochloric acid, continues to remove ethylene dichloride, takes off most solvent, adds proper amount of active carbon, stirs decolouring 1hr.
Suction filtration, the filtering insolubles.Add the 150ml ethylene dichloride in the filtrating, about 10 ℃, transfer solution PH >=11 with liquid caustic soda.Stir 30min, standing demix, water is with 100ml * 2 ethylene dichloride extraction secondary.Merge organic phase, once with the water washing of 100ml saturated common salt.Decompression removes ethylene dichloride, takes off most ethylene dichloride, and raffinate is used recrystallization from ethyl acetate/petroleum ether, gets 3-(3-fluoro-4-morpholinyl phenyl)-5-Qiang Jia Ji oxazolidine-2-ketone, pearl crystallization 21g, yield 82.9%.127～129 ℃ of product fusing points, optically-active-55 ° (C=0.99, chloroform).FAB-MSm/z:297.1[M+
Figure DEST_PATH_IMAGE038
](100).?'H-NMR(CDCL3,300MHz)δ:7.43(dd.1H,Ar-H),7.09(dd,!H,Ar-H),6.96(t,1H,Ar-H),4.73(m,3H,H-4-CH 2OH),3.87(t,4H,-CH 2OCH 2-),3.76(d,1H.4-H),3.06(t,4H,-CH 2NCH 2-)。
Embodiment two:
Except replacing the ethanol with Virahol, all the other obtain (R)-(+)-3-(3-fluoro-4-morpholine phenylamino)-1 with embodiment one, and the aqueous solution of 2-Ucar 35 can directly be used for step ring-closure reaction down.Through quantitative analysis, include (R)-(+)-3-(3-fluoro-4-morpholine phenylamino)-1,2-Ucar 35 19.04g.Yield 70.5%.
Embodiment three:
Except replacing three surpalites with two phosgene, all the other are with embodiment one.Get 3-(3-fluoro-4-morpholinyl phenyl)-5-Qiang Jia Ji oxazolidine-2-ketone, 20g, yield 67.6%.(with (S)-Racemic glycidol).
Embodiment four:
Except replacing three surpalites with the phosphinylidyne diimidazole and not the hydro-oxidation sodium de-acidying agent, all the other are with embodiment one.Get 3-(3-fluoro-4-morpholinyl phenyl)-5-Qiang Jia Ji oxazolidine-2-ketone, 20.86g, yield 70.5%.(in (S)-Racemic glycidol).
Embodiment five:
Except replacing 3-fluoro-4-(4-morpholinyl) aniline with 3-fluoro-4-(N-tert-butoxycarbonyl-piperazine base) aniline, molar ratio is constant, and all the other are with embodiment one.Obtain 3-［ 3-fluoro-4-(N-tert-butoxycarbonyl-piperazine base) phenyl ］-5-Qiang Jia Ji oxazolidine-2-ketone, 27.65g. yield 70%.(in (S)-Racemic glycidol).

Claims (9)

1. the preparation method of 3-substituted-phenyl-5-hydroxyl first base oxazolidine-2-ketone, the structural formula of said 3-substituted-phenyl-5-hydroxyl first base oxazolidine-2-ketone is:
Figure 2011102007143100001DEST_PATH_IMAGE002
In the formula, R 1Be halogen; R 2Be nitrogen heterocyclic ring or replacement aromatic ring;
Said nitrogen heterocyclic ring is
Figure DEST_PATH_IMAGE004
or
Figure DEST_PATH_IMAGE006
Z in the formula 1Be O, S or NR 4, R 4Be amine protecting group;
R 3Alkyl for C1-C4;
Said replacement aromatic ring is
Figure DEST_PATH_IMAGE008
Z wherein 2Be CH 2Or N; R 5For
Figure DEST_PATH_IMAGE010
Or ,
R wherein 6Alkyl for C1-C6; R 7Be amine protecting group; R 8Be amine protecting group;
It is characterized in that: the substituted aniline with structural formula II is a raw material,
R in the formula 1, R 2Definition the same,
Amino-1 through synthetic midbody (R)-(+)-3-substituted benzene that obtains of condensation reaction with Racemic glycidol, 2-Ucar 35, the structural formula of said Racemic glycidol do,
Said (R)-(+)-3-substituted benzene is amino-1, and the structural formula of 2-Ucar 35 does,
Figure DEST_PATH_IMAGE018
R in the formula 1, R 2Definition the same,
With the reaction of compound III and carbonyl derivative, promptly obtain target compound again, the structural formula of said carbonyl derivative does,
Wherein, X 2, X 3Be leavings group, be selected from halogen, the substituted C1 of halogen～C4 alkoxyl group, benzyloxy ,Phenoxy, ortho position or a position or contraposition halogen or substituted phenoxy of nitro or imidazolyl, X 2, X 3Can be identical, also can be different.
2. according to the preparation method of the said 3-substituted-phenyl-5-of claim 1 (R)-Qiang Jia Ji oxazolidine-2-ketone, it is characterized in that: in said substituted aniline and the Racemic glycidol reaction, substituted aniline is 0.8～5:1 with the ratio of the amount of substance of Racemic glycidol; Used organic solvent is selected from alcohol, ether or methane amide; Temperature of reaction is 20～100 ℃.
3. according to the preparation method of the said 3-substituted-phenyl-5-of claim 2 (R)-Qiang Jia Ji oxazolidine-2-ketone, it is characterized in that: substituted aniline is that the used organic solvent of 0.8～1.5:1 is selected from methyl alcohol, ethanol, Virahol, ether, THF, DIPE or DMF with the ratio of the amount of substance of Racemic glycidol; Temperature of reaction is 60～80 ℃.
4. according to the preparation method of the said 3-substituted-phenyl-5-of claim 1 (R)-Qiang Jia Ji oxazolidine-2-ketone, it is characterized in that: (R)-(+)-3-substituted benzene amino-1, the 2-Ucar 35 is 1:1～2 with the ratio of the amount of substance of carbonyl derivative; Used organic solvent is selected from alcohol, ether or methane amide; Temperature of reaction is-20～20 ℃.
5. according to the preparation method of the said 3-substituted-phenyl-5-of claim 4 (R)-Qiang Jia Ji oxazolidine-2-ketone, it is characterized in that: (R)-(+)-3-substituted benzene amino-1, the 2-Ucar 35 is 1:1.5 with the ratio of the amount of substance of carbonyl derivative; Used organic solvent is selected from methyl alcohol, ethanol, Virahol, ether, THF, DIPE or DMF; Temperature of reaction is-5～5 ℃.
6. according to the preparation method of the said 3-substituted-phenyl-5-of claim 1 (R)-Qiang Jia Ji oxazolidine-2-ketone; It is characterized in that: (R)-(+)-3-substituted benzene amino-1; In 2-Ucar 35 midbody and the carbonyl derivative VI reaction process; Add de-acidying agent, de-acidying agent is selected from mineral alkali or organic bases; The mol ratio of de-acidying agent and midbody is 0～4:1.
7. according to the preparation method of the said 3-substituted-phenyl-5-of claim 1 (R)-Qiang Jia Ji oxazolidine-2-ketone, it is characterized in that: de-acidying agent is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, pyridine, quinoline or triethylamine; The mol ratio of de-acidying agent and midbody is 0～2.4:1.
8. according to the preparation method of the said 3-substituted-phenyl-5-of claim 1 (R)-hydroxyl first base oxazolidine-2-ketone, it is characterized in that: said carbonyl derivative be selected from the adjacent chlorobenzene ester of phosgene, two phosgene, TRIPHOSGENE 99.5, methyl-chloroformate, Vinyl chloroformate, propyl chloroformate, butyl chlorocarbonate, chloroformic acid benzyl ester, methylcarbonate, diethyl carbonate, dipropyl carbonate, dibutyl carbonate, phenyl chloroformate, chloroformic acid, chloroformic acid to chlorobenzene ester, chloroformic acid m-chlorophenyl ester, the adjacent bromobenzene ester of chloroformic acid, chloroformic acid to bromobenzene ester, chloroformic acid bromochlorophene ester, chloroformic acid ortho-nitrophenyl ester, p-nitrophenyl chloroformate ester, chloroformic acid nitroxyl chloride phenyl ester, diphenyl carbonate, the two adjacent chlorobenzene esters of carbonic acid, the two m-chlorophenyl esters of carbonic acid, carbonic acid biconjugate chlorobenzene ester, the two adjacent bromobenzene esters of carbonic acid, carbonic acid two between bromobenzene ester, carbonic acid biconjugate bromobenzene ester, the two o-chloronitrobenzene esters of carbonic acid, the two m-nitro esters of carbonic acid, carbonic acid biconjugate nitro phenyl ester or phosphinylidyne diimidazole.
9. the preparation method of said according to Claim 8 3-substituted-phenyl-5-(R)-Qiang Jia Ji oxazolidine-2-ketone, it is characterized in that: said carbonyl derivative is selected from TRIPHOSGENE 99.5, two phosgene, phosgene, chloroformic acid benzyl ester, methyl-chloroformate, Vinyl chloroformate or phosphinylidyne diimidazole.
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CN103641790A (en) * 2013-12-24 2014-03-19 合肥星宇化学有限责任公司 Synthetic method of oxadiazon
CN103641790B (en) * 2013-12-24 2015-09-30 合肥星宇化学有限责任公司 The synthetic method of Yi Zhong Evil humulone
CN112409286A (en) * 2019-08-20 2021-02-26 杭州迪克科技有限公司 Synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone
CN112409286B (en) * 2019-08-20 2022-08-05 杭州迪克科技有限公司 Synthesis method of N-substituted phenyl-5-hydroxymethyl-2-oxazolidinone

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